My long term research interest is to investigate epigenetic mechanisms to suppress tumorigenesis. Recent studies suggest that the DMA damage response (DDR) induced by aberrant proliferation, may be one of the barriers at early stage of tumorigenesis to prevent genomic instability. One hallmark of DDR at early stage of tumorigenesis is histone H2A.X S139 phosphorylation (known as y-H2A.X). This phosphorylation event is well-known for its demarcation of compact chromatin structures formed during DDR induced byDMA damage agents. In keep with these observations, H2A.X deficiency accelerates the tumor progression on a p53 deficient background in mice. Our preliminary studies have identified a new mark phosphorylation on H2A.X, tyrosine 142 and its kinase, WSTF (William-Beuren Syndrome Transcription Factor), a gene frequently deleted in human William-Beuren Syndrome (WS). Our studies have demonstrated that WSTF has an intrinsic tyrosine kinase activity via its unconventional kinase domain, which shares no homology with any known kinase fold. Interestingly, our recent data indicate that the WSTF and ATM may form a "feed- forward" loop to regulate DDR induced by DNA damage treatment, including y-H2A.X (S139) phosphorylation. WSTF may also play a critical role in DDR initiated by aberrant proliferation;therefore, it may suppress tumorigenesis by preventing genomic instability. In the mentored phase, I will test if WSTF function is regulated by the ATM/R kinases. A parallel objective in this phase is to develop H2A.X "designer;chromatin" in collaboration with Dr. Tom Muir's lab (Rockefeller University). In the independent phase, I will test WSTF function for suppressing tumorigenesis in genetically modified mouse models. The goal of the mentored phase (I year) is to develop key methodologies and reagents for the independent phase and beyond. At the same time, I will apply for independent positions. The excellent environment in Drs. Allis and Muir's lab will facilitate my research in the mentored phase and my transition to an independent investigator. The proposed research at the independent phase (3 years) will pave the road to launch my future investigations to identify novel epigenetic mechanisms to suppress tumorigenesis. RELEVANCE: Investigation of WSTF function in preventing genomic instability and tumorigenesis will reveal new mechanisms in human cancer. In addition, these studies will shed light on the molecular mechanisms leading to human William Syndrome, an intractable neurodevelopmental disease.